Project Summary/Abstract The progression from damaged DNA and its cellular processing to mutagenesis during DNA replication is a complex process. Depending upon the nature of the mutations and the genes affected the further progression to a tumor can be even more complex. The initial damage may have occurred in unusual DNA sequences or structures that are refractory to repair, it may be embedded in chromatin structures that restrict access to repair enzymes and occasionally, the primary causal event may be an undamaged DNA sequence that has been processed incorrectly by transcription and/or replication. The 2014 Gordon Research Conference on DNA damage, mutation and cancer will focus on the manner in which DNA lesions and unusual DNA structures can be recognized and processed by cellular enzymes to modulate their mutagenic effects. Multiple proteins may recognize the same DNA alteration and impact the pathway choice for its resolution. Furthermore, each step in a repair pathway generates another lesion, often accessible to enzymes from other pathways. Crosstalk between competing or collaborating DNA repair pathways will be an important theme in this Conference. We will also explore chemotherapeutic interventions to take advantage of potential genotypic differences between normal cells and those in a designated tumor. The synthetic lethality approach is important, but there are other approaches to selectively inactivate tumor cells in the sea of normal cells. We will also address the evidence for the role of DNA damage in aging, and the importance of telomere processing in aging and cancer. The nine provisional sessions are titled: Mutations cause cancer, reveal etiology and provide clues for therapy; Sensing environmental genomic damage, finding needles in the haystack; Weak links in the genome, intrinsic challenges to replication and transcription; Cutting edges at the initiation of DNA repair; Oxidative DNA damage and base excision repair, roles of PARP; Mismatch repair and responses to arrested replication or transcription; Cell cycle checkpoints and strand-break repair; Designing chemotherapies based upon cancer genotypes; and Relationships of DNA damage to telomere maintenance and aging. Poster sessions and open afternoons will provide ample opportunities for engagement between investigators at all levels. We anticipate that scientific interactions during this conference will impact cancer research in significant ways and result in establishing productive multi-disciplinary research collaborations. The 2014 DNA Damage, Mutation & Cancer Gordon Research Conference will be held at the Beach Marriott, in Ventura, California March 16 - 21, on the 50th anniversary of the reported discovery of excision repair and the 40th anniversary of the first international workshop on DNA repair mechanisms.